MXPA06015036A

MXPA06015036A - Diaminooxidase-containing pharmaceutical compositions.

Info

Publication number: MXPA06015036A
Application number: MXPA06015036A
Authority: MX
Inventors: Albert Missbichler; Franz Gabor; Herwig Reichl
Original assignee: Albert Missbichler
Priority date: 2004-07-07
Filing date: 2005-07-06
Publication date: 2007-04-25
Also published as: US20100330191A1; US9364437B2; US20080193491A1; JP2008505869A; US20140220148A1; CN1980689A; DE502005009568D1; SI1763363T1; PT1763363E; EP1763363B1; DK1763363T3; AT502098B8; EP1782824A3; PL1763363T3; EP1782824B1; CY1109351T1; EP1782824A2; AT503070B1; ATE467423T1; AT503070A1

Abstract

The invention relates to pharmaceutical compositions, food supplement compositions and cosmetic compositions which contain diaminooxidase and to the use thereof.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING DIAMINOOXIDASE DESCRIPTION OF THE INVENTION The present invention relates to compositions for the treatment and / or prevention of diseases and conditions induced by histamine. Histamine (lH-imidazol-4-ethylamine) is formed by the enzymatic decarboxylation of histidine and, thus, is a basic biogenic amine having a molecular weight of 111 Da. In the body, histamine appears practically ubiquitously. This is produced by humans themselves and stored inactive in the metachromatic granules of mast cells and basophilic leukocytes, where it is available for immediate release. The highest concentrations of hietamine are measured in the lungs. After its release, histamine is a highly potent mediator for a plurality of physiological and pathophysiological processes, often also by means of an interaction with cytokines. In addition, histamine can also enter the body from the outside, by inhalation, on the one hand, or orally, for example, by ingesting histamine-containing foods, such as cheese, wine, canned fish and sourdough. REF: 178130 The most important function and effects of histamine in the human and animal body, respectively, are: 1) Dilation of capillaries, increase in capillary permeability and decrease in blood pressure. 2) Contractions of the smooth muscles, for example, of the bronchial muscles in the lungs. 3) Induction of an increase in gastric acid secretion. 4) Increase in heart rate. 5) Histamine is the mediator of the immediate type allergic reaction, this is the most important mediator in allergic diseases, such as allergic rhinitis (hay fever) and bronchial asthma. 6) In addition, histamine is the classic trigger for hives (nettle itch) and plays an important role in drug allergies or intolerances. High concentrations of freely circulating histamine initiate unwanted effects, such as headaches, blocked nose or excess nasal flow, obstruction of the respiratory tract, tachycardia as well as extrasystoles, and also, gastrointestinal pains that can induce loose stools until diarrhea, and hypotension. Often also swelling of the eyelids, sometimes also urticarial rashes have been described. In addition, reddening of the skin, a decrease in blood pressure and Bronchospasm may occur. The following table shows the symptoms as a function of the concentration of histamine in blood.

In the mammalian organism, histamine is degraded by two enzymes: diaminooxidase (DAO, EC 1.3.4.6) and histamine-N-methyltransferase (NMT, EC 2.1.1.8) (Mizugushi et al., 1994). DAO catalyzes the oxidative deamination of histamine to imidazole-acetaldehyde; NMT catalyzes N-methylation to N-methylhistamine. Both degradation pathways are essential for the organism: DAO eliminates histamine which, for example, has been collected in the gastrointestinal tract via food, NMT controls the transmission of histaminergic signals in the nervous system (Kitanaka et al, 2002). The main objective of DAO is to prevent the histamine that has been ingested with food from reaching the intestines into the bloodstream. Failure of this protective mechanism should result in anaphylactic shock in extreme cases (Taylor 1986, Nilsson et al., 1996). DAO is a secretory protein and, thus, acts extracellularly, whereas N-methyltransferase is exclusively active in the cytosol (Küfner et al., 2001). Native DAO, which can degrade additional biogenic amines, such as, for example, putrecin, spermidine and cadaverine, in addition to histamine, and which may be, for example, recovered from the porcine kidney, is a glycoprotein containing homodimeric copper, in which the sub-units are connected via disulfide bonds. DAO has a molecular weight of approximately 182 kDa (Kluetz and Schmidt, 1997, Rinaldi et al., 1982) and a carbohydrate portion of approximately 11% (Shah and Ali, 1988). The enzyme belongs to the class of copper-containing aminooxidases, which catalyze the oxidative deamination of primary amines to aldehydes, ammonia and hydrogen peroxide according to the following general reaction scheme (Bachrach 1985): RCH2NH2 + H20 + 02? RCHO + NH3 + H202, the residue R contains an amino group. Characteristics of aminooxidases that have Copper is a topaquinone in the active center that is formed by post-translational modification of a conserved tyrosine residue (James et al., 1990, James et al., 1992; Mu et al., 1992). DAO is mainly found in the small intestine, in the liver, in the kidneys and in the blood in white blood cells. In pregnant women, DAO is additionally formed in the placenta. Pregnant women have a blood DAO level that is higher by approximately 500 to 1000 times that of non-pregnant women. DAO is continuously produced and excreted into the intestinal lumen. In healthy humans, foods rich in histamines are therefore already largely released from histamine in the intestines. The remaining histamine is degraded as it passes through the intestinal mucosa through the DAO present there. Histamine is decomposed to imidazole acetaldehyde and, in addition, to imidazole acetoacetic acid. The co-factors of DAO are 6-hydroxycopa and presumably pyridoxal phosphate, vitamin B6. DAO is a sensitive enzyme that can be inhibited by various substances, for example, by biogenic amines, alcohol and its degradation product of acetaldehyde, and various medications. In neuronal tissue, up to now, DAO activity can not be detected. As previously mentioned here, the Hexamine histamine ingested with food, but also endogenous histamine, can trigger a wide variety of disorders due to allergic reactions. With respect to its clinical value, at least three forms of a histamine intolerance based on reduced DAO activity have to be noted: Few people have a deficiency of congenital DAO and do not lose it. During an infection of the intestinal mucosa, a transient DAO deficiency may occur. When the infection has been healed, DAO activity also returns to normal. When various activity inhibiting substances are administered, reduced DAO activity can result exogenously. Among them are mainly alcohol and its degradation product, acetaldehyde, certain food products rich in amines and many medicines. In all cases, the initially described symptoms occur more or less easily and can not be easily attributed in the majority of cases. A rapid classification of the functional activity of the enzyme allows rapid and simple therapy and to provide an appropriate dietary plan. A frequent reason for the appearance of a Histamine intolerance is the sensitivity of the enzyme in relation to a large number of chemical substances. Many of them appear in different medications. Most of the important DAO inhibitors are acriflavine, diazepam, N-methyl-N-formylhydrazine, b-aminopropionitriles, dimaprit, O-methylhydroxylamine, agmantine, ethanol (10%), pargyline, aldomet, furosemide, fenamil, amiloride, guanabez , phenelzine, aminoguanidine, guanfacine, phenformin, amitriptyline, guanidine, feniprazine, amodiaquine, haloperidol, prometiazine, anserine, hiamine 1622, propanolol, aziridinyl-alkyl-amines, hydroxychloroquines, pyrimidine Bl, hydroxylamine, quinacrine, burimamide, impromidine, semicarbazide, cadaverine , imidazole derivatives, thiamines, carnosine, iproniazid, thioridazine, chlorothiazide, isocarboxazide, tranilcipramin, chlorpromazine, isoniazid, trimethoprim, cimetidine, metiamide, tryptamine, clonidine, metronidazole, tyramine, cyanide, nazlinin (alkaloid), diamines (also histamine) and Nt-methyl-histamine. In WO 02/43745 the systemic use of DAO of plant origin for the treatment of histamine-mediated diseases is described. The administration of DAO or enzymes in general that are directly isolated from plants is a big problem to the frequent appearance of allergens in plants, mainly in view of the fact that fact that the legume plants described in WO 02/43745 have a high allergenic potential. An objective of the present invention is to provide compositions for the treatment and prevention of histamine-induced diseases and conditions that do not have the side effects of products available on the market., which mainly contain cortisone, and which eliminate the disadvantage found in the prior art mentioned above. A further objective of the present invention is further to increase the concentration of the active diaminooxidase within the body, in particular in the gastrointestinal tract, of an individual to help with this in or make possible respectively the degradation particularly of histamine. which has been exogenously administered (for example, with food). Therefore, the present invention relates to pharmaceutical compositions for the treatment of histamine-induced diseases comprising diaminooxidase, wherein the composition is provided in an application form for epidermal, oral, peroral or sublingual administration as a hydrogel, gastric juice-resistant pellet, drops, in particular ophthalmic drops and nasal drops, or as a tablet, food supplement compositions, or dietetic food products and cosmetic compositions comprising diaminooxidase. In the compositions according to the invention, the diaminooxidase is substantially provided in its active form, which means that the enzymes which, for example, do not comprise copper in their prosthetic group, and at least do not show wild-type activity, are not suitable for the applications according to the invention. The pharmaceutical composition according to the invention comprises a pharmaceutical form that allows administration selected from the group consisting of epidermal, oral, peroral and sublingual administration. The epidermal administration of DAO is mainly advantageous in the case of diseases induced by histamine, or conditions, respectively, on the surface of the skin, or on the outermost layers of the skin, respectively, since this is, for example, possible successfully treat allergic reactions that resulted from a skin contact with an allergen. Likewise, the itching caused in various diseases, such as urticaria, atopic eczema and the like, triggered by a histamine release, may be stopped. By oral and peroral administration of the compositions according to the invention, it is possible to introduce DAO into the gastrointestinal tract of an individual and to successfully have or treat, respectively, the histamine-induced disease there by degradation of histamine. The range of activity of the DAO is mainly restricted to the gastrointestinal tract, since the high content of acid in the stomach has a negative effect on DAO activity. Therefore, when DAO is administered orally or orally, it is necessary to protect DAO from gastric acid until it has reached the gastrointestinal tract. However, if DAO is administered sublingually, the enzyme is rapidly collected in the mouth by the oral mucosa and distributed to the bloodstream. In this way it is possible to quickly and easily transfer DAO into the bloodstream without having to transport the enzyme intravenously, or having to transport it through the stomach to the intestines without any damage, which delays a quick indication of the effect of the enzyme. The pharmaceutical composition is provided in a form of administration selected from the group consisting of hydrogel, pellet resistant to gastric juice, drops, in particular ophthalmic drops and nasal drops, tablets and capsules. According to the present invention, it is possible to convert DAO by processing methods according to those known in the prior art, in pharmaceutical forms to be administered. Therefore, the pharmaceutical compositions comprising DAO also contain additional ingredients which are used to stabilize the enzyme, on the one hand, and to carry the enzyme to the corresponding galenical form, on the other hand. DAO can therefore also be administered together with other pharmaceutically active substances in a simple form of administration, or separately, as long as the enzyme is not inhibited by any of these active substances, such that an activity of the enzyme does not display its desired effect. The hydrogel compositions comprising DAO according to the invention, preferably have a viscosity of 0.5 to 5 cp (centipoise), more preferably 1 to 2 cp, in particular 1.1 to 1.6 cp, at a shear rate of 41 seconds " 1 wherein the measurement can be performed by means of viscosimeters known in the prior art It has been found that the hydrogel composition containing DAO has advantageous properties (eg, topical distribution ability, good handling) particularly in these viscosity ranges At a lower viscosity of 0.5 cp, the hydrogel composition proved that it is too thin in order to allow user-friendly handling of the preparation, preferably polyacrylates (eg, carbopol), cellulose derivatives, or modified cellulose. , respectively, in particular, hydroxyethylcellulose (for example, natrosol), methylcellulose, hydroxypropylmethylcellulose and hydroxymethylcellulose, starch and modified starch, natural and synthetic rubbers, such as for example, tragacanth, guar, carrageenan, gelatin, sodium alginate, PVP, polyvinyl alcohol and mixtures thereof, are used as gelatinization agents. As the gelatinization agent, hydroxyethylcellulose (for example, Natrozole) is particularly preferably used, in particular, the Natrosol type 250 HHR shows a particularly good stability even at a low concentration. The pH of the hydrogel composition is preferably in the range of 7.0 to 9.0, preferably 7.2 to 8.5, more preferably 7.5 to 8.0. This pH range is preferably adjusted with a buffer, in particular with a Bis / Tris buffer, where additional salts (eg, 20-300 mM, preferably 50-200 mM, in particular 100 mM sodium chloride) can be added to maintain the activity and stability of the DAO enzyme If the total concentration of the salts is below 20 mM, the DAO has a poorer stability that can lead to a loss of activity. be preservative aggregates to the hydrogel composition according to the invention, which preservatives substantially prevent the proliferation of microorganisms in the composition.What is important here is to choose the preservatives such that the antimicrobial substances do not inhibit the DAO activity in a manner that its enzymatic activity is no longer sufficient to achieve the objective of the present invention (degradation of histamine). Through activity tests that are carried out with DAO and the conservative, such substances can be identified. Preferably, chlorhexidine, parabens (para-hydroxy-benzoic acid esters, in particular butyl-, ethyl-, methyl- or propyl-parabens), benzoates (for example, sodium benzoate), sorbates (for example) are used as preservatives. , potassium sorbates), carbamates (eg, iodopropynyl-butyl carbamate) and combinations thereof (eg, Rokosonal = mixture of sodium benzoate, potassium sorbate and iodopropynyl butyl carbamate). Particularly preferred are hydrogel compositions comprising natrosol as a gelatinization agent and Rokosonal and / or parabens as preservatives. Of course, according to the invention can also be added essences and aromatic substances that are used in the cosmetics industry, for example. A further aspect of the present invention relates to a food supplement composition, or a dietary food product (DFS) that is adapted as a pellet resistant to gastric juice, drops or infusion. The oral administration of DAO by means of a food, a dietary supplement, or a dietary product requires that this enzyme enters that part of the body in which its activity is going to be displayed. Since histamine plays an important role in the gastrointestinal tract, it is necessary that the DAO be adapted or provided in a way that can pass the stomach with high acid content, without damage. In this instance, the DAO is preferably processed to a pellet resistant to gastric acid. Since at a pH below 3, the DAO is irreversibly damaged (the pH in the stomach is in the range of pH 2 and 4), in order to transport the DAO through the stomach to the intestinal tract is necessary that the DAO be provided in an appropriate form of administration (the pharmaceutical composition or composition of the food supplement, or dietetic food product, respectively). According to the invention, the capsules (for example, gelatin capsules) and, in particular, pellets resistant to gastric juices have proven to be particularly advantageous. It is an advantage if the activity of the DAO starts 15 minutes later, preferably 20 minutes later, in particular 30 minutes later, after having been administered. According to the invention, "resistant to gastric acid" is to denote that the property of the pellet that is capable of protecting an active substance (for example, DAO) contained therein under the action of a gastric juice or a solution having properties comparable to those of gastric juice (for example, for a certain period of time of at least 10, preferably at least 20, more preferably at least 30, in particular at least 60 minutes such that the active substance suffers a loss 50% activity, most preferably 40% at most, more preferably 30% at most, more preferably 20% at most, in particular 10% at most, preferably after 20 minutes in particular after 30 minutes, the pellet according to the invention releases in the intestines at least 60%, in particular at least 80% of the DAO activity that was used to formulate the pellets.The pellets resistant to gastric juices are pellets that are coated by a coating resistant to gastric juice, which dissolves at a pH as found in the intestinal tract.This means that such coatings are preferably dissolved at a pH of at least 4 and 10 at most. dragit, for example, a coating resistant to gastric juice based on anionic polymers of methacrylic acid and methacrylates, contains -COOH as a functional group and dissolves in the range of pH 5.5 to pH 7. As an alternative, to Eudragit, gum arabic or the acetylated starch (for example, Amprac 01) can be used. Since the coatings resistant to juices Gastric, known in the prior art, have different properties (for example pH at which the coating dissolves, dissolution rate) the materials of the coatings can also be combined. The gum arabic, for example, shows good resistance to acid, yet it dissolves very slowly in the gastrointestinal tract. Amprac 01, on the other hand, dissolves rapidly in the intestinal environment, is not yet sufficiently acid resistant. In order to compensate for the disadvantages of a material, the two aforementioned materials can, for example, be blended at a weight ratio of 60-95 / 40-5, preferably 70-90 / 30-10, shellac / Amprac 01. An additional parameter that has an influence on the release rate of the active substance is the thickness of the layer of the pellet resistant to gastric juice. The thickness of the layer, expressed as mass proportion, is preferably 5 to 30%, more preferably 10 to 20%, of the total mass of the final product. The pellets preferably have an average diameter of 0.5 to 5 mm, in particular of 0.7 to 2 mm. Such size has the advantage that the pellets can quickly pass the stomach. The preparation of the pellets of the invention that can be used in the pharmaceutical composition of the invention and a food supplement composition of the invention, or food or dietetic product, respectively, is preferably effected by means of an extruder which requires a thermal stability of the ingredients of the composition, in particular of the given active substance, up to 60 ° C. (Stricker Arzneiformenentwicklung, Springer Verlag 2003). The pellets may comprise additional pharmaceutical additives in addition to the coating resistant to gastric juice, and DAO. For example, microcrystalline cellulose (Avicel, for example) serves as a filler and swelling agent. Cellulose is insoluble in water, and in this form it has crystalline and also amorphous portions. This combination causes a plastic deformation, which means that at a sufficiently high force, a reversible change in shape will occur. This is a substantial prerequisite for the formation of the pellets in an extruder and spheronizer. During wet-based granulation, microcrystalline cellulose absorbs large amounts of water and thus becomes a ily compressible cohesive mass, also without the addition of an agglutinate. According to the invention, the amount of microcrystalline microcellulose in a pellet can be in the range of between 5 and 70%, preferably between 10 and 60%, even more preferably between 15 and 50%. As the filler binder, sucrose can be used. Sucrose inces the solubility of the matrix and thus helps in the rapid release of the enzyme. According to the invention, sucrose can be added to a pellet in an amount of 1 to 40%, preferably 1 to 35%, even more preferably 10 to 30%. Hydroxypropylcellulose (mixed in an amount preferably of 0.5 to 10%) can also be added as a binder, and serves to prevent fine dust. In addition, hydroxypropylcellulose increases the resistance of the pellet and, in this way, contributes again to the improvement of the yield. The corn starch can be added to the pellet according to the invention as a filler and disintegrating agent (in a preferred amount of 1 to 30%). Being a substance insoluble in water, the starch can absorb a large amount of water and, thus, is an ideal disintegrating agent. Croscarmellose (Na-CMC; Acdisol) is a pure disintegrating agent, which preferably can be used in an amount between 1% and 5%. A too high portion of Acdisol will lead to an early disintegration of the pellet already during the rounding of the pellet and, thus, is counterproductive. Crospovidone, a cross-linked PVP, is also insoluble in water and also serves as a disintegrating agent. Due to its polymeric properties, it helps in an improved rounding during the production of the pellets (it can be mixed preferably in an amount of 0.5 to 10%). The Povidone is a water soluble additive and serves as a binder. The combination of these different fillers, disintegrating agents and binders leads to a dispersed molecular distribution of the DAO in the pellet, and ensures a rapid bioavailability. Between the gastric juice resistant coating and the pellet with the active agent, an insulating layer made of glycerol and / or talc can be provided. Glycerol serves as a humectant to prevent dehydrogenation and, thus, inoculation of the enzyme. As an alternative to pellets, DAO can also be transported in capsules through the stomach to the gastrointestinal tract. Suitable capsules are, for example, gelatin capsules or starch capsules. The capsules may also contain the pellets according to the invention. A further aspect of the present invention relates to a cosmetic composition comprising diaminooxidase, which is provided in a cosmetic composition form, in particular as a hydrogel, ointment, spray or as drops. In the case of an increased release of histamine, or in the case of contact with allergenic substances (for example, in the case of contact allergies or neurodermatitis), bodily reactions may occur in visible body sites, Reactions can be suppressed by administration of DAO in cosmetic compositions. The cosmetic compositions comprising DAO may also comprise other ingredients known in the prior art that are used in the preparation of cosmetic products. The cosmetic compositions comprising hydrogel have substantially the same properties and contain substantially the same ingredients as the hydrogels of a pharmaceutical composition according to the invention. Preferably, the diaminooxidase used in the compositions according to the invention is of origin, not vegetable. The use of DAO of non-vegetable origin in pharmaceutical and cosmetic compositions, as well as in food supplements and dietetic products has the advantage that the allergens that appear in plants will not negatively affect the administration of DAO, since the allergens substantially promote the release of endogenous histamine. It has been known that mainly vegetable substances are responsible for the diseases induced by histamine. The complete elimination of the ingredients that trigger the allergy of a DAO preparation of vegetable origin is possible only with a high preparative effort, while the DAO according to the invention which is of non-vegetable origin, is completely free of such plant allergens. According to the present invention, by "non-vegetable origin" are included all the DAOs that are not recovered from plants, but from animal or other non-plant organisms. Furthermore, according to the invention this definition includes all DAOs that are recombinantly prepared in cell cultures (animals, bacteria, yeast and the like), or in non-plant organisms of any type, while the DNA of the DAO recombinantly prepared is isolated of plant and / or animal organisms by methods known in the prior art, and cloned and expressed in expression systems. Preferably, all compositions described in the present invention comprise diaminooxidase of animal origin. Through the use of animal DAO, it is possible to provide the human or animal body, respectively, with an enzyme that is very similar to the enzyme produced by these individuals in terms of the glycosylation, activity and specificity of the DAO produced by these individuals themselves. . It is also possible to completely exclude plant allergens from the production of DAO. Preferably, the diaminooxidase is recovered from the porcine kidneys. Porcine kidneys are mainly characterized by their high DAO content.

From the porcine kidneys, the enzyme can be isolated in a simple manner by methods known in the prior art. According to a further preferred embodiment, the compositions according to the invention comprise diaminooxidase of recombinant origin. By recombinant reproduction of DAO it is possible to produce large amounts of enzyme and purify this enzyme with a high yield. Preferably, the recombinant diaminooxidase is expressed in prokaryotes, preferably in bacteria, or in eukaryotes, preferably in the culture of animal or yeast cells and isolated from the expression systems indicated above. The purification of DAO produced by means of these expression systems, which is either expressed in the cells or is secreted from the cells during expression, is effected by methods known in the prior art. In doing so, DAO with a peptide (e.g., His tag), polypeptide or protein sequence (e.g., GST tag) is also possible to simplify such purification. The recombinant DAO can also be modified by genetic engineering methods, such that the enzymatic activity of this DAO exceeds the enzymatic activity of the wild-type DAO.

A further aspect of the present invention relates to the use of the diaminooxidase according to the invention to produce a medicament for the treatment of clinical conditions induced by histamine. It is known that DAO is responsible for the degradation of histamine in the human and animal body. Since the diseases induced by histamine are caused by an excess of histamine, it is due to the lack of diaminooxidase or the inhibition of DAO, or due to an excess of histamine which, as a rule, can be caused by food and also by additional extrinsic factors, such as, for example, contact with allergens, the administration of DAO thus lends itself to the treatment of these diseases, or clinical conditions, respectively. A further aspect of the present invention relates to the use of the diaminooxidase of the invention to produce a medicament for the treatment of urticaria, in particular chronic and acute urticaria. With urticaria, a release of histamine causes a widening of the venules and an excessive permeability of the capillaries with a resulting edema. By administering DAO to the area of the affected skin, it is possible to degrade the histamine in the affected sites and thereby stop the itching of the urticaria. A further aspect of the present invention relates to the use of the diaminooxidase of the invention for produce a medication for the treatment of contact allergies. Contact allergies are caused by substances (allergens) that trigger allergic reactions when they penetrate into the skin. In order to degrade the histamines released by this contact, and thereby stop or relieve, respectively, the clinical pictures induced by histamine, DAO is administered. According to a further aspect of the present invention, a diaminooxidase according to the invention is used to produce a medicament for the treatment of atopic dermatitis. Atopic dermatitis, also known by the name of neurodermatitis, is a frequent skin disease associated with pronounced itching that occurs mainly in children and young adults. The cause of this itching is the excessive release of histamine from the affected sites of the skin. Also in this case, DAO can contribute to the reduction of histamines in these areas and, in this way, alleviate or prevent, respectively, the symptoms of atopic dermatitis. According to a further aspect, the present invention relates to the use of the diamonooxidase of the invention to produce a medicament for the treatment of scombrotoxism. Scombrotoxism is a histamine poisoning after consumption of mackerel varieties, for example, tuna. When the cold chain is interrupted, or When the preparation is delayed, so-called scombrotoxins are formed in the scombroids, which leads to an enrichment of the histamine. The consequences of this histamine poisoning are, for example, fever, nausea, vomiting, stomach pain and urticaria. In this case, DAO can be used as a detoxifying agent. A further aspect of the present invention relates to the use of the diaminooxidase of the invention to produce a medicament or a dietary supplement, or for a dietetic product, to eliminate histamine from the gastrointestinal tract, or reduce it therein, respectively. The reduction of histamine in the intestinal tract is of particular importance in the case of an increased supply of histamine (exogenous supply, for example, per food) to the body of an individual or for example if the activity of DAO in the intestinal tract is partially or entirely undue or not provided at all, respectively. The medicament, or dietary supplement, or dietetic food product, respectively, of the invention serves in this way to supply enzymatically active DAO which contributes to the degradation of histamine in the intestinal tract. A further aspect of the present invention relates to the use of diaminooxidase to produce a medicament for eliminating histamine from the bronchial system.

Ingestion of histamine releasing substances, such as, for example, pollen, within the bronchial system, or within the lungs, respectively, can lead to pronounced allergic reactions. In order to degrade the released histamine, the DAO of the invention can, for example, be introduced into the bronchial system, or into the lungs, respectively, by inhalation spray or the like. The invention will be further explained by the following examples, however, without being restricted thereto.

EXAMPLES Example 1 The DAO was actively stabilized in a cellulose based pellet, and the pellet was coated with a gastric juice resistant coating. In the dissolution test, it could show that more than 70% of the activity is achieved towards the surroundings within the first hour.

Example 2 In addition, the enzyme was stabilized in a hydrogel. Storage at room temperature and at 37 SC did not show a decrease in activity within 4 months. The appearance of vesicles and itching of the skin After stimulation with histamine it disappeared a few minutes after the application of the hydrogel.

Example 3 DAO stabilized in the hydrogel was tested in a total of 13 people. As a questionnaire, it was distinguished between contact allergy stress (n = 5), neurodermatitis / dermatosis (n = 6) and insect bites (n = 2). In all patients with contact allergies and in patients with neurodermatitis, a positive effect was attested; in the case of insect bites, 50% of volunteers could report a positive effect.

The effect of the hydrogel occurred within the first 10 minutes, the effect on average lasted for more than an hour.

No volunteer reported uncomfortable effects in the case of repeated application. Two patients with neurodermatitis stated that the hydrogel of the invention was more effective than a cortisone ointment used at that time.

Example 4 Pellets resistant to gastric juice were prepared with 3% DAO having an initial activity of 80,000 U / ml, 40% microcrystalline cellulose, 20% sucrose, 22% other binders, fillers and disintegrating agents, and with % of a coating resistant to gastric juice. The release of DAO from the pellets was observed for a period of 180 minutes by means of an activity assay. Here, in the solution in which the pellets had been dissolved, after 10 minutes a DAO activity of 40% was detected, after 30 minutes, an activity of 70%, after 80 minutes, an activity of 180 minutes an activity of 100% of the amount of DAO originally used. The measurement of DAO activity as described in AT 411688, where, however, other known methods for measuring enzymatic activity could also be employed.

REFERENCES: Bachrach U., in: B. Mondovi (Ed) (1985), Structure and Functions of Amine Oxidase, CRC Press, Boca Raton, pp. 5-2Ox Bartholomew M.J. et al (1990), Cancer 66: 1539-1543 James S.M., Palcic M.M. , Scaman C.H., Smith A.J., Brown D.E., Dooley D.M. , Mure M., Klinman J.P. (1992), Bio-chemistry 31: 12147-12154 James S.M., Mu D., Wemmer D., Smith A.J., Kaur S., Maltby D., Burlingame A.L., Klinman J.P. (1990), Science 248: 981-987 Keskinege A., Elgun S., Yilmaz E. (2001), Biochim. Biophys. Acta 25:76 Kitanaka J., Kitanaka N., Tsujimura T., Terada, N., Takemura M. (2002), European Journal of Pharmacology 437: 179-185 Kluetz M.D., Schmidt P.G. (1977), Biochem. Biophys. Res. Comm. 76: 40-45 Küfner M.A. , Ulrich P., Raithel M., Schwelberger H.G. (2001), Inflamm. beef. 50, Supplement 2, 96-97 Kusche J., Menningen R., Leisten L., Krakamp B. (1988), Adv. Exp. Med. Biol. 250: 745-52 Kusche J., Bieganski T., Hesterberg R., Stahlknecht C.D., Feussner K.D., Stahlenberg I., Lorenz W. (1980), Agents Actions 10: 110-3 Mennigen R, Bieganski T, Elbers A, Kusche J (1989), J. Chromatogr. B Biomed. Sci. Appl. 27: 221 Mizuguchi H., Imamura I., Takemura M., Fukui H. (1994), J.

Biochem. 116: 631-635 Mu D., James S.M., Smith A.J., Brown D.E., Dooley D.M., Klinman J.P. (1992), J. Biol. Chem. 267: 7979-7982 Nilsson B.O., Kockum I., Rosengren E. (1996), Inflammation Res. 45: 513-518 Rinaldi A., Vecchini P., Floris G. (1982), Prep. Biochem. 12: 11-28 Shah M. A., Ali R. (1988), Biochem. J. 253: 103-107 Taylor S.L. (1986), Crit. Rev. Toxicol. 17: 91-128 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A pharmaceutical composition for the treatment of histamine-induced diseases, comprising diaminooxidase, characterized in that the composition is provided in an application form for oral, or peroral epidermal administration as a hydrogel, as a pellet resistant to gastric juices, as a capsule or tablet resistant to gastric juices.

2. A food supplement composition, characterized in that it comprises diaminooxidase.

3. A dietetic food product, characterized in that it comprises diaminooxidase.

4. A composition according to claim 2 or 3, characterized in that the composition is provided in the form of a pellet resistant to gastric juices, a capsule or tablet resistant to gastric juices.

5. A cosmetic composition, characterized in that it comprises diaminooxidase.

6. A composition in accordance with the claim 5, characterized in that the composition is provided in a cosmetic application form, in particular as a hydrogel.

7. A composition according to any of claims 1 to 6, characterized in that the diaminooxidase is of non-vegetable origin.

8. A composition according to claim 7, characterized in that the composition comprises diaminooxidase of animal origin.

9. A composition according to claim 8, characterized in that the diaminooxidase is derived from porcine kidney.

10. A composition according to any of claims 1 to 9, characterized in that the composition comprises diaminooxidase of recombinant origin.

11. A composition according to claim 10, characterized in that it comprises recombinant diaminooxidase recovered from prokaryotic cell cultures, preferably bacterial, or eukaryotic, preferably animal or yeast cultures.

12. The use of diaminooxidase to produce a medicament for the treatment of clinical conditions induced by histamine, wherein the medicament is provided in an application form for epidermal, oral or peroral administration as a hydrogel, as a pellet resistant to gastric juices, a capsule or tablet resistant to gastric juices.

13. The use of diaminooxidase to produce a medicament for the treatment of urticaria, in particular chronic and acute urticaria, wherein the medicament is provided in the form of application for epidermal, oral or peroral administration as a hydrogel, as a pellet resistant to gastric juices, capsule or tablet resistant to gastric juices.

14. The use of diaminooxidase to produce a medicament for the treatment of contact allergy, wherein the medicament is provided in an application form for epidermal administration as a hydrogel.

15. The use of diaminooxidase to produce a medicament for the treatment of atopic dermatitis, wherein the medicament is provided in an application form for epidermal, oral or peroral administration as a hydrogel, as a pellet resistant to gastric juices, a capsule or tablet resistant to gastric juice.

16. The use of diaminooxidase to produce a medicament for the treatment of scombrotoxism, wherein the medicament is provided in a form of application for oral or peroral administration as a pellet resistant to gastric juices, a capsule or tablet resistant to gastric juices.

17. The use of diaminooxidase to produce a medicament for eliminating histamine from the gastrointestinal tract, wherein the medicament is provided in an application form for oral or peroral administration as a pellet resistant to gastric juices, a resistant capsule or tablet to the gastric juices.

18. The use of diaminooxidase to produce a medicament for eliminating histamine from the bronchial system, wherein the medicament is provided as drops or spray.